Raynaud Phenomenon (RP) causes vasospasm of the thermoregulatory arterioles in cold-exposed hands and feet of affected persons, resulting in numb, ischemic digits and pain, adversely affecting quality of life1 and there is currently no effective topical product available to patients for acute treatment or for prevention. A characteristic blanching with clear demarcation occurs, accompanied by numbness and discomfort occurring due to ischemia, followed by bluish discoloration then redness when blood flow returns (hyperemia). After a cold challenge, recovery of perfusion is slower in RP patients. The nipple of the breast may also be affected very painfully.
Causes of RP include autoimmune disorders such as but not limited to: scleroderma, systemic lupus erythematosus, mixed connective-tissue disease, dermatomyositis, polymyositis, rheumatoid arthritis and Sjögren syndrome.2 According the Scleroderma Association of Saskatchewan, RP affects approximately 90% of people with scleroderma.3 Lupus erythematosus, affecting about 1 in 1000 Canadians, can also present with symptoms of Raynaud phenomenon.4 An association with some medications, diabetes and occupational vibration exposure has also been noted. Primary RP (not related to connective tissue disease) also affects at least 3-7% of the population worldwide. For example, some drugs, including beta blockers (which may be used to treat high blood pressure), migraine medications that contain ergotamine or sumatriptan, attention-deficit/hyperactivity disorder medications, certain chemotherapy agents, and drugs that cause blood vessels to narrow (such as some over-the-counter cold medications) have been linked to Raynaud's phenomenon.
There may be familial tendency in some cases and it is more common in adult females.1,5 While not wishing to be limited by theory, the pathogenesis of primary RP involves peripheral alpha-2 adrenoreceptors5(b) and disorders of the vascular system's thermoregulatory mechanisms.6 Family history, migraines and smoking are also related to the incidence of primary RP.1 
RP is always not a benign condition: in severe cases associated with certain connective tissue or autoimmune diseases, diabetes and/or drug exposures, tissue damage with ulceration and even necrosis may occur due to repeated and prolonged ischemia. For example, most patients with scleroderma suffer severe RP requiring medical treatment.7 A survey of 443 subjects with self-reported RP from 15 countries found that 64 percent of subjects reported a poor or very poor current ability to prevent or control RP attacks.8 Cold avoidance may not even be possible, for example, in patients with certain occupations.
When pharmacological treatment is initiated due, for example, to severe disease impact on quality of life, when preventative measures are insufficient and/or when tissue damage such as ulceration is occurring, an object of therapy is to reduce the severity and/or frequency of attacks.9 For example, patients with secondary RP (disease-related, e.g. 90% of patients with scleroderma) are more likely to have severe attacks and require pharmacologic treatment10, including oral vasodilators, calcium channel blockers11, oral or topical nitrates, fluoxetine, phosphodiesterase-5 inhibitors12, beta-blockers and local injections of botulinum A toxin.13 Surgical sympathectomy of the hands may be used in resistant cases.14 Oral calcium channel blockers are often front-line therapy for RP15, and evidence-based reviews of the effectiveness of calcium channel blockers indicate that nifedipine appears to be superior to nicardipine in that drug class in reducing the frequency and severity of attacks in primary RP16, whereas reviews of oral vasodilators show very limited effectiveness.17 However, oral nifedipine has several constraints. To be effective, it must be taken on a daily basis but there is a risk of systemic adverse effects, such as flushing or dizziness, and the drug may not be as effective at a more tolerable dose. During an attack, oral dosing may not result in rapid relief due to the lag time for absorption.
A topical formulation for immediate as-needed use in patients with RP may avoid daily oral dosing, or could be used, for example as an adjunct therapy in more severe cases. An advantage of topical application of nifedipine would be that an immediate effect may, for example, be achieved on the local tissue and systemic exposure would be limited. However, for treatment of RP with topical agents, there is little available. Chung et al. performed a double-blind placebo controlled trial of a topical nitroglycerin product in patients with RP. While they found a significant difference between treatment and placebo in the clinical scoring of RP overall, there was no statistical difference in the duration, severity or subjective assessment of the RP attacks.18 This is consistent with the lack of superiority of oral nitrates in the treatment of RP.19 Nitrates, both topical and oral, are associated with headaches and flushing.20 Furthermore, the well-known issue of pharmacological tolerance to nitrates with chronic dosing21 has not been addressed in this clinical context. Nifedipine, however, does have good evidence of efficacy and its mechanism in RP is well understood.22 
Local pharmacy-prepared topical nifedipine has sometimes been requested by physicians for use by patients but it was not stable due to the UV-light sensitivity of the drug, leading to inconsistent efficacy.23 Furthermore, nifedipine is not water soluble, which may, for example, present certain limitations to the pharmacist such as having to use hydrophobic cream bases or having to perform relatively complex compounding procedures.
In general, a topical formulation is used either to treat the skin itself or as an alternative to other dosing routes for local tissues. The outermost layer of skin, the stratum corneum, is a barrier to absorption. Drugs can penetrate the skin through hair follicles or, for very lipophilic and small molecules, pass directly through the epithelium, but this is very limited. Penetration enhancers are compounds which facilitate transdermal drug absorption such as by affecting epithelial tight junctions,24 and thus are commonly employed in topical formulations which are intended to facilitate drug passage into the dermal layer or beyond. For example, the penetration enhancer diethylene glycol monoethyl ether (Transcutol HP®) has an established safety record25, regulatory approval for human use and ease of incorporation into emulsions.
An emulsion may, for example, allow certain actives to be readily incorporated into the internal oil phase, while a non-greasy feel is still achieved. For patient acceptability, an oily topical preparation is generally not desirable for use on the hands and feet. However, a potential concern with emulsions in general is the tendency for coalescence of the oil droplets of the internal phase. If this occurs, long-term stability is reduced. The composition and viscosity are features which may be used to minimize the potential for phase separation.
Topical medications are applied to external body surfaces and therefore have the potential for significant light exposure. Typically, these preparations are applied as a thin film, maximizing the surface area of the formulation to light and therefore the potential to interact with UV light. A recent analysis of topical products in the United States Pharmacopoeia and the European medicines databases indicated that up to 28% of approved drugs have the recommendation to protect the product from light26 and the list of new drugs with this recommendation continues to grow.27 While some drug products are simply inactivated by light exposure, resulting in subpotency, others may form photodegradation products with toxicities or unknown effects.28 Exposure of nifedipine to UVA light results in the formation of dehydronifedipine followed by dehydronitrosonifedipine29, compounds which are inactive as vasodilators. Variable amounts of UV-induced degradation of nifedipine occur during preparation and storage. Light exposure may also influence the physical and/or technical performance of a topical formulation, such as but not limited to changes in viscosity, precipitation of components, changes in emulsion droplet size affecting stability and/or changes in chemical degradation of materials.26 
Photostabilizers are chemicals that filter UV energy by absorbing a certain range of high energy UV wavelengths and releasing the energy at a lower range. In doing so, however, the photostabilizers degrade unless used in combination. UV blockers include rutin and quercetin (antioxidant compounds found in fruits and vegetables)30 and butyl methoxydibenzoylmethane (BMDBM; an approved sunscreen agent also known as avobenzone).31 These compounds dissolve into the oil phase of an oil-in-water (o/w) emulsion. In addition to its use as a photostabilizer, quercetin has also been used for wound healing32.
Nifedipine may also be useful to treat conditions related to peripheral vascular insufficiency. Such conditions include venous leg ulceration due to sustained venous hypertension, which results from chronic venous insufficiency33, intermittent claudication and peripheral arterial occlusive disease. The great majority of vascular ulcers are chronic or recurrent. They cause a considerable amount of morbidity among patients with peripheral vascular disease, including work incapacity. Additionally, these non-healing ulcers may place the patient at much higher risk for lower extremity amputation.